tbuckley/cabot-search huggingface dataset:
Phenotypic effects of genetic variants associated with autism
Authors: Thomas Rolland, Freddy Cliquet, Richard J. L. Anney, Clara Moreau, Nicolas Traut, Alexandre Mathieu, Guillaume Huguet, Jinjie Duan, Varun Warrier, Swan Portalier, Louise Dry, Claire S. Leblond, Elise Douard, Frédérique Amsellem, Simon Malesys, Anna Maruani, Roberto Toro, Anders D. Børglum, Jakob Grove, Simon Baron-Cohen, Alan Packer, Wendy K. Chung, Sébastien Jacquemont, Richard Delorme, Thomas Bourgeron
Journal: Nature Medicine (2023)

Abstract While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis of autism. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Based on data from more than 13,000 individuals with autism and 210,000 undiagnosed individuals, we estimated the odds ratios for autism associated to rare loss-of-function (LoF) variants in 185 genes associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the correlates of these variants in individuals without a diagnosis of autism. We show that these variants are associated with a small but significant decrease in fluid intelligence, qualification level and income and an increase in metrics related to material deprivation. These effects were larger for autism-associated genes than in other LoF-intolerant genes. Using brain imaging data from 21,040 individuals from the UK Biobank, we could not detect significant differences in the overall brain anatomy between LoF carriers and non-carriers. Our results highlight the importance of studying the effect of the genetic variants beyond categorical diagnosis and the need for more research to understand the association between these variants and sociodemographic factors, to best support individuals carrying these variants.
Iron homeostasis imbalance and ferroptosis in brain diseases
Authors: Haining Long, Wangshu Zhu, Liming Wei, Jungong Zhao
Journal: MedComm (2023)

Brain iron homeostasis is maintained through the normal function of blood-brain barrier and iron regulation at the systemic and cellular levels, which is fundamental to normal brain function. Excess iron can catalyze the generation of free radicals through Fenton reactions due to its dual redox state, thus causing oxidative stress. Numerous evidence has indicated brain diseases, especially stroke and neurodegenerative diseases, are closely related to the mechanism of iron homeostasis imbalance in the brain. For one thing, brain diseases promote brain iron accumulation. For another, iron accumulation amplifies damage to the nervous system and exacerbates patients' outcomes. In addition, iron accumulation triggers ferroptosis, a newly discovered iron-dependent type of programmed cell death, which is closely related to neurodegeneration and has received wide attention in recent years. In this context, we outline the mechanism of a normal brain iron metabolism and focus on the current mechanism of the iron homeostasis imbalance in stroke, Alzheimer's disease, and Parkinson's disease. Meanwhile, we also discuss the mechanism of ferroptosis and simultaneously enumerate the newly discovered drugs for iron chelators and ferroptosis inhibitors.
G-MDSC-derived exosomes mediate the differentiation of M-MDSC into M2 macrophages promoting colitis-to-cancer transition
Authors: Yungang Wang, Hongli Liu, Zhe Zhang, Dezhi Bian, Keke Shao, Shengjun Wang, Yanxia Ding
Journal: Journal for ImmunoTherapy of Cancer (2023)

In inflammatory bowel disease microenvironment, transdifferentiation of myeloid-derived suppressor cells (MDSCs) and M2 macrophage accumulation are crucial for the transition of colitis-to-cancer. New insights into the cross-talk and the underling mechanism between MDSCs and M2 macrophage during colitis-to-cancer transition are opening new avenues for colitis-associated cancer (CAC) prevention and treatment.The role and underlying mechanism that granulocytic MDSCs (G-MDSCs) or exosomes (Exo) regulates the differentiation of monocytic MDSCs (M-MDSCs) into M2 macrophages were investigated using immunoﬂuorescence, FACS, IB analysis, etc, and employing siRNA and antibodies. In vivo efficacy and mechanistic studies were conducted with dextran sulfate sodium-induced CAC mice, employed IL-6 Abs and STAT3 inhibitor.G-MDSCs promote the differentiation of M-MDSC into M2 macrophages through exosomal miR-93-5 p which downregulating STAT3 activity in M-MDSC. IL-6 is responsible for miR-93-5 p enrichment in G-MDSC exosomes (GM-Exo). Mechanistically, chronic inflammation-driven IL-6 promote the synthesis of miR-93-5 p in G-MDSC via IL-6R/JAK/STAT3 pathway. Early use of IL-6 Abs enhances the effect of STAT3 inhibitor against CAC.IL-6-driven secretion of G-MDSC exosomal miR-93-5 p promotes the differentiation of M-MDSC into M2 macrophages and involves a STAT3 signaling mechanism that promote colitis-to-cancer transition. Combining STAT3 inhibitors with strategies that inhibit IL-6-mediated G-MDSC exosomal miR-93-5 p production is beneficial for the prevention and treatment of CAC.
Posterior scleral birefringence measured by triple-input polarization-sensitive imaging as a biomarker of myopia progression
Authors: Xinyu Liu, Liqin Jiang, Mengyuan Ke, Ian A. Sigal, Jacqueline Chua, Quan V. Hoang, Audrey WI. Chia, Raymond P. Najjar, Bingyao Tan, Jocelyn Cheong, Valentina Bellemo, Rachel S. Chong, Michaël J. A. Girard, Marcus Ang, Mengyang Liu, Gerhard Garhöfer, Veluchamy A. Barathi, Seang-Mei Saw, Martin Villiger, Leopold Schmetterer
Journal: Nature Biomedical Engineering (2023)

Abstract In myopic eyes, pathological remodelling of collagen in the posterior sclera has mostly been observed ex vivo. Here we report the development of triple-input polarization-sensitive optical coherence tomography (OCT) for measuring posterior scleral birefringence. In guinea pigs and humans, the technique offers superior imaging sensitivities and accuracies than dual-input polarization-sensitive OCT. In 8-week-long studies with young guinea pigs, scleral birefringence was positively correlated with spherical equivalent refractive errors and predicted the onset of myopia. In a cross-sectional study involving adult individuals, scleral birefringence was associated with myopia status and negatively correlated with refractive errors. Triple-input polarization-sensitive OCT may help establish posterior scleral birefringence as a non-invasive biomarker for assessing the progression of myopia.
Characterization of intratumoral tertiary lymphoid structures in pancreatic ductal adenocarcinoma: cellular properties and prognostic significance
Authors: Xuan Zou, Xuan Lin, He Cheng, Yusheng Chen, Ruijie Wang, Mingjian Ma, Yu Liu, Zhengjie Dai, Yesboli Tasiheng, Yu Yan, Qinqin Hou, Fei Ding, Huan Chen, Xianjun Yu, Xu Wang, Chen Liu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Tumor-associated tertiary lymphoid structures (TLSs) are functional immune-responsive niches that are not fully understood in pancreatic ductal adenocarcinoma (PDAC).Fluorescent multiplex immunohistochemistry was performed on sequential sections of surgically resected tumor tissues from 380 PDAC patients without preoperative treatment (surgery alone (SA)) and 136 patients pretreated with neoadjuvant treatment (NAT). Multispectral images were processed via machine learning and image processing platforms, inForm V.2.4 and HALO V.3.2; TLS regions were segmented, and the cells were identified and quantified. The cellular composition and immunological properties of TLSs and their adjacent tissues in PDAC were scored and compared, and their association with prognosis was further examined.Intratumoral TLSs were identified in 21.1% (80/380) of patients in the SA group and 15.4% (21/136) of patients in the NAT group. In the SA group, the presence of intratumoral TLSs was significantly associated with improved overall survival (OS) and progression-free survival. The existence of intratumoral TLSs was correlated with elevated levels of infiltrating CD8+T, CD4+T, B cells and activated immune cells in adjacent tissues. A nomogram model was generated with TLS presence as a variable, which successfully predicted PDAC patient OS in an external validation cohort (n=123). In the NAT group, samples exhibited a lower proportion of B cells and a higher proportion of regulatory T cells within intratumoral TLSs. Additionally, these TLSs were smaller in size, with a lower overall maturation level and reduced immune cell activation, and the prognostic value of TLS presence was insignificant in the NAT cohort.Our study systematically revealed the cellular properties and prognostic values of intratumoral TLSs in PDAC and described the potential impact of NAT on TLS development and function.
Multi-level analysis of the gut–brain axis shows autism spectrum disorder-associated molecular and microbial profiles
Authors: James T. Morton, Dong-Min Jin, Robert H. Mills, Yan Shao, Gibraan Rahman, Daniel McDonald, Qiyun Zhu, Metin Balaban, Yueyu Jiang, Kalen Cantrell, Antonio Gonzalez, Julie Carmel, Linoy Mia Frankiensztajn, Sandra Martin-Brevet, Kirsten Berding, Brittany D. Needham, María Fernanda Zurita, Maude David, Olga V. Averina, Alexey S. Kovtun, Antonio Noto, Michele Mussap, Mingbang Wang, Daniel N. Frank, Ellen Li, Wenhao Zhou, Vassilios Fanos, Valery N. Danilenko, Dennis P. Wall, Paúl Cárdenas, Manuel E. Baldeón, Sébastien Jacquemont, Omry Koren, Evan Elliott, Ramnik J. Xavier, Sarkis K. Mazmanian, Rob Knight, Jack A. Gilbert, Sharon M. Donovan, Trevor D. Lawley, Bob Carpenter, Richard Bonneau, Gaspar Taroncher-Oldenburg
Journal: Nature Neuroscience (2023)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut-brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD.
Agricultural activities and risk of treatment for depressive disorders among the entire French agricultural workforce: the TRACTOR project, a nationwide retrospective cohort study
Authors: Pascal Petit, Gérald Gandon, Marc Dubuc, Nicolas Vuillerme, Vincent Bonneterre
Journal: The Lancet Regional Health - Europe (2023)

Although depression is a major issue among farming population, to date, there have been few studies on specific agricultural activities. We aimed to investigate whether, among the entire French farm manager (FM) workforce, certain agricultural activities are more strongly associated with depression than others.This nationwide retrospective cohort study used data from an administrative health database available to the TRACTOR project. This database pertains to the entire French agricultural workforce (overseas workers not included). Data were analyzed from January 2021 to December 2022. All FMs that worked at least once over the period 2002-2016 were included. The outcome measure was the association between 26 agricultural activities and the risk of depression measured as hazard ratios (HRs) after adjusting for age, sex, and pre-existing medical comorbidities. The time to first depression insurance declaration, or first antidepressant prescription claim was used as the underlying timescale. For each activity, the reference/control group included all FMs that never performed the considered activity between 2002 and 2016, while the exposed group included FMs that performed the considered activity at least once from 2002 to 2016. Four sensitivity analyses were conducted to test hypotheses, and to address potential sources of bias.There were 84,507 (7.76%; 28.2 cases per 1000 person-years) depression cases among 1,088,561 FMs (mean age 46.6 [SD 14.1]). Compared to other activities, dairy farming (HR = 1.37, 95% confidence interval: 1.32-1.42), cow farming (HR = 1.53 [1.47-1.59]), poultry and rabbit farming (HR = 1.37 [1.27-1.50]), and mixed farming (HR = 1.30 [1.24-1.36]) were more strongly associated with depression. Sex differences were observed, with most of the time, risks higher for females than for males.Agricultural activities at risk of depression among the entire French agricultural workforce were identified. These findings do represent a crucial first step on the road to implement effective preventive measures against depression to determine where additional resources should be allocated to screen for depression, along with intervention.MIAI@Grenoble Alpes, and Mutualité Sociale Agricole.
Brain metabolism in Alzheimer’s disease: biological mechanisms of exercise
Authors: Longfei Xu, Ran Liu, Yingkai Qin, Tianhui Wang
Journal: Translational Neurodegeneration (2023)

Alzheimer's disease (AD) is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors, accompanied by dysregulation of numerous intracellular signaling and molecular pathways in the brain. At the cellular and molecular levels, the neuronal cellular milieu of the AD brain exhibits metabolic abnormalities, compromised bioenergetics, impaired lipid metabolism, and reduced overall metabolic capacity, which lead to abnormal neural network activity and impaired neuroplasticity, thus accelerating the formation of extracellular senile plaques and intracellular neurofibrillary tangles. The current absence of effective pharmacological therapies for AD points to the urgent need to investigate the benefits of non-pharmacological approaches such as physical exercise. Despite the evidence that regular physical activity can improve metabolic dysfunction in the AD state, inhibit different pathophysiological molecular pathways associated with AD, influence the pathological process of AD, and exert a protective effect, there is no clear consensus on the specific biological and molecular mechanisms underlying the advantages of physical exercise. Here, we review how physical exercise improves crucial molecular pathways and biological processes associated with metabolic disorders in AD, including glucose metabolism, lipid metabolism, Aβ metabolism and transport, iron metabolism and tau pathology. How metabolic states influence brain health is also presented. A better knowledge on the neurophysiological mechanisms by which exercise improves AD metabolism can contribute to the development of novel drugs and improvement of non-pharmacological interventions.
Exosomal circRNA: emerging insights into cancer progression and clinical application potential
Authors: Fan Zhang, Jiajia Jiang, Hui Qian, Yongmin Yan, Wenrong Xu
Journal: Journal of Hematology & Oncology (2023)

Abstract Exosomal circRNA serves a novel genetic information molecule, facilitating communication between tumor cells and microenvironmental cells, such as immune cells, fibroblasts, and other components, thereby regulating critical aspects of cancer progression including immune escape, tumor angiogenesis, metabolism, drug resistance, proliferation and metastasis. Interestingly, microenvironment cells have new findings in influencing tumor progression and immune escape mediated by the release of exosomal circRNA. Given the intrinsic stability, abundance, and broad distribution of exosomal circRNAs, they represent excellent diagnostic and prognostic biomarkers for liquid biopsy. Moreover, artificially synthesized circRNAs may open up new possibilities for cancer therapy, potentially bolstered by nanoparticles or plant exosome delivery strategies. In this review, we summarize the functions and underlying mechanisms of tumor cell and non-tumor cell-derived exosomal circRNAs in cancer progression, with a special focus on their roles in tumor immunity and metabolism. Finally, we examine the potential application of exosomal circRNAs as diagnostic biomarkers and therapeutic targets, highlighting their promise for clinical use.
DCATS: differential composition analysis for flexible single-cell experimental designs
Authors: Xinyi Lin, Chuen Chau, Kun Ma, Yuanhua Huang, Joshua W. K. Ho
Journal: Genome biology (2023)

Differential composition analysis - the identification of cell types that have statistically significant changes in abundance between multiple experimental conditions - is one of the most common tasks in single cell omic data analysis. However, it remains challenging to perform differential composition analysis in the presence of flexible experimental designs and uncertainty in cell type assignment. Here, we introduce a statistical model and an open source R package, DCATS, for differential composition analysis based on a beta-binomial regression framework that addresses these challenges. Our empirical evaluation shows that DCATS consistently maintains high sensitivity and specificity compared to state-of-the-art methods.
Les fondements biologiques de la psychologie.
Authors: Jean Lhermitte
Journal: JAMA (1926)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
California’s State Insurance Gender Nondiscrimination Act and Utilization of Gender-Affirming Surgery—Reply
Authors: Anna Schoenbrunner, Annamarie Beckmeyer, Adrian Diaz
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
CD19-Targeting CAR T Cells for Myositis and Interstitial Lung Disease Associated With Antisynthetase Syndrome
Authors: Ann-Christin Pecher, Luca Hensen, Reinhild Klein, Rebekka Schairer, Katrin Lutz, Daniel Atar, Christian Seitz, Anna Stanger, Janine Schneider, Christiane Braun, Marina Schmidt, Marius Horger, Antje Bornemann, Christoph Faul, Wolfgang Bethge, Joerg Henes, Claudia Lengerke
Journal: JAMA (2023)

Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were efficacious as an immune suppressive agent in 6 patients with refractory systemic lupus erythematosus and in 1 patient with antisynthetase syndrome.To test the safety and efficacy of CD19-targeting CAR T cells in a patient with severe antisynthetase syndrome, a complex autoimmune disorder with evidence for B- and T-cell involvement.This case report describes a patient with antisynthetase syndrome with progressive myositis and interstitial lung disease refractory to available therapies (including rituximab and azathioprine), who was treated with CD19-targeting CAR T cells in June 2022 at University Hospital Tübingen in Tübingen, Germany, with the last follow-up in February 2023. Mycophenolate mofetil was added to the treatment to cotarget CD8+ T cells, hypothesized to contribute to disease activity.Prior to treatment with CD19-targeting CAR T cells, the patient received conditioning therapy with fludarabine (25 mg/m2 [5 days before until 3 days before]) and cyclophosphamide (1000 mg/m2 [3 days before]) followed by infusion of CAR T cells (1.23×106/kg [manufactured by transduction of autologous T cells with a CD19 lentiviral vector and amplification in the CliniMACS Prodigy system]) and mycophenolate mofetil (2 g/d) 35 days after CD19-targeting CAR T-cell infusion.The patient's response to therapy was followed by magnetic resonance imaging of the thigh muscle, Physician Global Assessment, functional muscle and pulmonary tests, and peripheral blood quantification of anti-Jo-1 antibody levels, lymphocyte subsets, immunoglobulins, and serological muscle enzymes.Rapid clinical improvement was observed after CD19-targeting CAR T-cell infusion. Eight months after treatment, the patient's scores on the Physician Global Assessment and muscle and pulmonary function tests improved, and there were no detectable signs of myositis on magnetic resonance imaging. Serological muscle enzymes (alanine aminotransferase, aspartate aminotransferase, creatinine kinase, and lactate dehydrogenase), CD8+ T-cell subsets, and inflammatory cytokine secretion in the peripheral blood mononuclear cells (interferon gamma, interleukin 1 [IL-1], IL-6, and IL-13) were all normalized. Further, there was a reduction in anti-Jo-1 antibody levels and a partial recovery of IgA (to 67% of normal value), IgG (to 87%), and IgM (to 58%).CD19-targeting CAR T cells directed against B cells and plasmablasts deeply reset B-cell immunity. Together with mycophenolate mofetil, CD19-targeting CAR T cells may break pathologic B-cell, as well as T-cell responses, inducing remission in refractory antisynthetase syndrome.